Project Summary The goal of this application is to examine the relationship between threat- and reward-related neural circuitries and symptom dimensions of anxiety and depression during the transition from adolescence to adulthood. This project is in line with the Research Domain Criteria's (RDoC) objective of identifying new strategies for psychiatric classification based on observable dimensions and their corresponding neural circuitries. We have identified a tri-level model of symptom dimensions that includes a broad factor (General Distress) common to all anxiety and depressive symptoms, as well as factors of intermediate breadth (Fears, Anhedonia-Apprehension) that are more distinctive to subsets of anxious and depressive symptoms. Existing research highlights dysregulation of a threat-related neural circuit encompassing the amygdala and subgenual portion of the anterior cingulate cortex in both anxiety and depression. Distinctions between anxiety and depression may be present in a reward-related neural circuit encompassing the ventral striatum and orbitofrontal cortex, which appears elevated in anxiety but reduced in depression. By studying both reward- and threat-related brain function, we will address RDoC constructs of Positive Valence (reward sensitivity) as well as Negative Valence (threat sensitivity). We will prospectively examine whether neural profiles predict the course of symptoms, and conversely, whether symptom courses covary with changes in neural activation over 36 months. Taking a vulnerability-stress perspective, we will test whether life-stress moderates the prospective associations between neural profiles and symptom trajectories. In addition, we will evaluate whether neural data possess predictive value above and beyond other indices of threat and reward sensitivity, including self- report, behavioral, and physiological measures. Results are expected to a) enhance our understanding of threat- and reward-related dysregulation in anxiety and depression, b) identify intermediate neural phenotypes that are not limited to existing diagnostic criteria, c) facilitate more targeted pharmacological and neurofeedback based treatments, d) contribute to a classification system for anxiety and depression that is informed by contemporary science, and e) evaluate the precision with which neural data can cross-sectionally and longitudinally classify individuals into empirically established symptom and impairment profiles. To achieve these aims, we will use self-report measures of threat and reward sensitivity to select 18 to 19 year olds who represent the full range on each dimension. Symptoms, impairment, and life stress will be assessed at baseline, 12-months, 24 months, and 36 months, and fMRI scanning of threat- and reward-related brain function will occur at baseline and 36 months. Participants will be recruited from local communities at two sites, UCLA (n=125) and Northwestern University (n=125) when they are 18 to 19 years old.